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NATIONAL ACADEMY OF SCIENCES WALTER ABRAHAM JACOBS 1883—1967 A Biographical Memoir by ROBERT C. ELDERFIELD Any opinions expressed in this memoir are those of the author(s) and do not necessarily reflect the views of the National Academy of Sciences. Biographical Memoir COPYRIGHT 1980 NATIONAL ACADEMY OF SCIENCES WASHINGTON D.C. WALTER ABRAHAM JACOBS December 24, 1883-July 12, 1967 BY ROBERT C. ELDERFIELD ALTER ABRAHAM JACOBS died in Los Angeles after a Wlong and impressive career. He left behind some 273 publications which record important contributions in the field of the chemistry of natural products of biological im- portance, as well as the development of chemotherapeutic agents-the significance of which was not recognized until some years had passed. Jacobs was born in New York City on December 24, 1883 and attended local elementary schools. He received an A.B. degree in 1904 and an A.M. in 1905 from Columbia Univer- sity, after which he enrolled at the University of Berlin for study under Emil Fischer, earning a Ph.D. degree in 1907. On his return to New York, Jacobs received an appoint- ment as a fellow in chemistry in the laboratory of Phoebus A. Levene at the newly established Rockefeller Institute for Medical Research. In 1908 he became an assistant, and in 1910 an associate in Levene's laboratory. During these years with Levene, he was closely associated with the latter's work on the chemistry of the nucleic acids. The studies, first with the nucleotide inosinic acid from beef extract, disclosed its essential chemistry by hydrolysis to the nucleoside, inosine, and by subsequent cleavage from the latter of its crystalline sugar component which was identified 248 BIOGRAPHICAL MEMOIRS as D-ribose. This became the pattern for similar studies with the nucleotide guanylic acid, and with yeast nucleic acid (ribonucleic acid), from which the various nucleosides were then isolated and interpreted. The attempted extension of this procedure to similar studies with thymus nucleic acid (subsequently shown to be desoxyribosenucleic acid) was in- terrupted by Jacobs' promotion in 1912 to associate member of the Institute with independent status. Dr. Simon Flexner, Director of the Institute, felt that the developing field of chemotherapy warranted a division of its own, and Jacobs was placed in charge of it. In collaboration with Michael Heidelberger, he began an investigation of the possible chemotherapy of polio. It was known that hexameth- ylenetetramine apparently exerted a slight therapeutic effect, and an extended series of quaternary salts was prepared by reaction with aromatic and alipathic halogen compounds. Some of the salts displayed bactericidal properties, and a few appeared to prolong the life of polio-infected monkeys. Un- fortunately, this was due to a loss of virulence of the virus strain. After the disappointing outcome of the chemotherapeutic studies concerning polio, the JacobsHeidelberger team turned its attention to African sleeping sickness, for which no effective and non-toxic drugs were available. Ehrlich had produced a powerful synthetic agent against trypanosomiasis in para-arsenophenylglycine, in which the arsenic was tri- valent. The analogous pentavalent substance, para-phenyl- glycine arsonic acid, was considerably less toxic, but devoid of activity against the disease. Jacobs reasoned that the lack of activity could be due to the free carboxyl group which con- ceivably could react with many centers of the tissue proteins before reaching the parasites. He therefore proposed mask- ing the carboxyl group by conversion to the amide. The resulting substance, sodium para-phenylglycine amide ar- WALTER ABRAHAM JACOBS 249 sonate, was the first, simplest, and best arsenical of a series subsequently synthesized. The new arsenical, named Tryparsamide by Simon Flexner, was found to be extremely effective in trypanosome infected animals by Drs. Wade H. Brown and Louise Pearce, who now formed part of the chemotherapeutic team. Several patents were awarded for control of the drug and several of its analogs-although none of the latter proved to be supe- rior to Tryparsamide. At the conclusion of World War I, Louise Pearce made an extensive study of the drug in the Belgian Congo, which showed Tryparsamide to be more ef- fective than previously used drugs. Further tests in the United States demonstrated some utility in the treatment of tertiary syphilis. Some years later (1953), Belgium recognized the successes of Tryparsamide by making Drs. Jacobs, Heidelberger, Brown and Pearce officers of the Order of Leopold 11. During World War I, a portion of the Institute was desig- nated as U.S. Laboratory # 1, and served as a training facility in laboratory techniques for army physicians. Jacobs and Hei- delberger investigated possible synthetic substitutes for Sal- varsan, a drug in scant supply and of undesirable toxicity. One analog (arsenophenyl-glycine-bis-m-hydroxyanilide), which appeared to be less toxic and at least as active against syphilis when studied by Brown and Pearce in animals, showed promising results in some one hundred human syphilitics. Unfortunately, a second batch, for no apparent reason, caused severe, dangerous dermatitis and was aban- doned. At the conclusion of the work on arsenicals, Jacobs and Heidelberger desired to turn to fields other than synthetic organic chemistry, but Flexner's faith in this approach pre- vailed and attention was turned to pneumococcal and strep- tococcal infections. The drug, Optochin, had been used with 250 BIOGRAPHICAL MEMOIRS partial success in the treatment of pneumococcal infections, SO further modification of the cinchona alkaloids was investi- gated, and a long series of papers resulted. Unfortunately, most of these substances killed infected mice faster than drug or infection alone. The state of this area of chemistry in the United States at the time is reflected in the refusal of the Journal of the American Chemical Society to publish the work on the cinchona alkaloids--on the grounds that no one in Amer- ica was interested in alkaloids. Only after long arguments were the manuscripts accepted. One of the intermediates used in modification of the alkaloids and in other syntheses was p-aminobenzene- sulfonamide, or sulfanilamide, which had been prepared in 1908 by Gelmo in Germany. This was shown by Trefouel, Trefouel, Nitti, and Bovet to be one of the metabolic prod- ucts of the azo dye Prontosil, the antibiotic action of which w,as demonstrated in the same year (1935) by Gerhardt Domagk for which he was awarded the Nobel Prize. Actually, it developed that the antibiotic action of Prontosil was due to the sufanilamide liberated on metabolism of Prontosil. It ap- parently never occurred to Jacobs and Heidelberger in 1920 that such a simple substance could control bacterial infections by other than direct antibacterial action. If the antibiotic ac- tion had been recognized, many thousands of lives could have been saved in the intervening years. After some nine and one-half years, the team of Jacobs and Heidelberger separated. Flexner agreed that chemo- therapeutic research through synthetic methods could be abandoned, and Heidelberger was transferred to the new laboratory of Donald D. Van Slyke to become familiar with biochemistry. Jacobs became a full member of the IRocke- feller Institute in 1923, and turned his attention to the eluci- dation of the structures of substances of natural origin which displayed powerful physiological actions in order to correlate WALTER ABRAHAM JACOBS 25 1 structure with such activity. The name of the laboratory was changed to that of chemical pharmacology. The first group explored was that known as the cardiac glycosides, noted for their specific and powerful action on the myocardium, and which are unrivaled in value for the treat- ment of congestive heart failure. Of the group, the glycosides from digitalis species are probably the best known. Extracts of other plants containing members of the group such as strophanthus species were used as arrow poisons by African tribes. The ancient Egyptians were familiar with the proper- ties of squill, and the Romans used it as an emetic, heart tonic, diuretic and rat poison. Strophanthus was introduced into modern medicine in 1890, and the modern use of digitalis dates from 1785, when William Withering published his famous book entitled, An Account of the Foxglove and Some of Its Medicinal Uses: With Practical Remarks on Dropsy and Other Dis- eases. At the time Jacobs began his investigations on the struc- tures of these important compounds, little was known of them or their chemistry. It was known that they were glyco- sides consisting of a rather complicated aglycone moiety, which was responsible for their major pharmacological prop- erties, joined with one or more sugar molecules. The digitalis glycosides are present in the plant in extremely small amounts, whereas the seeds of Strophanthus kombi are rela- tively rich in the glycosides of strophanthidin. Jacobs' plan of attack on the structures of the aglycones was to place major emphasis on the structure determination of the more acces- sible strophanthidin and to attempt a correlation of this struc- ture with the digitalis aglycones and others by chemical inter- conversions of appropriate derivatives. This plan proved to be completely successful and the structures of a half dozen or so of the aglycones were demonstrated. It should be noted that when the study of the cardiac 252 BIOGRAPHICAL MEMOIRS. aglycones was begun (1923), similar studies on cholesterol and the bile acids by Windaus (1903), Diels (1903) and Wie- land (1912) in Germany were also under way. There was no reason to believe that the th'ree groups of substances would ultimately be found to be closely related. Also, with the pos- sible exception of ultraviolet spectroscopy, none of the instru- mental methods, such as infrared spectroscopy, X-ray spec- troscopy and nuclear magnetic resonance, were available. Chemical transformations and degradation with subsequent interpretation formed the basis for structural elucidati~on-a long and tedious process at best.

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